Chemotherapy of
leishmaniasis is mainly based on antimonials. However, they are extremely toxic and cause serious side effects, and there is a worldwide increasing frequency of chemoresistance to antimonials. These issues emphasize the urgent need for affordable alternative drugs against
leishmaniasis. Leishmania
cysteine proteases are essential for parasite growth, differentiation, pathogenicity, and virulence and are thus attractive targets for combating
leishmaniasis. Herein we demonstrate that the
cysteine protease inhibitors aziridine-2,3-dicarboxylates 13b and 13e impaired promastigote growth at mid-micromolar concentrations and decreased the
infection rate of peritoneal macrophages at concentrations 8- to 13-fold lower than those needed to inhibit parasite replication. Simultaneous treatment of infected cells with compound 13b and
gamma interferon resulted in an even further reduction of the concentration needed for a significant decrease in macrophage
infection rate. Notably, treatment with the compounds alone modulated the
cytokine secretion of infected macrophages, with increased levels of
interleukin-12 and
tumor necrosis factor alpha. Furthermore, the decreased
infection rate in the presence of compound 13b correlated with increased
nitric oxide production by macrophages. Importantly, at the concentrations used herein, compounds 13b and 13e were not toxic against fibroblasts, macrophages, or dendritic cells. Together, these results suggest that the aziridine-2,3-dicarboxylates 13b and 13e are potential antileishmanial lead compounds with low toxicity against host cells and selective
antiparasitic effects.